Eight-fold signal amplification of a superconducting nanowire single-photon detector using a multiple-avalanche architecture

Superconducting nanowire avalanche single-photon detectors (SNAPs) with n parallel nanowires are advantageous over single-nanowire detectors because their output signal amplitude scales linearly with n. However, the SNAP architecture has not been viably demonstrated for n > 4. To increase n for larger signal amplification, we designed a multi-stage, successive-avalanche architecture which used nanowires, connected via choke inductors in a binary-tree layout. We demonstrated an avalanche detector with n = 8 parallel nanowires and achieved eight-fold signal amplification, with a timing jitter of 54 ps

A superconducting-nanowire 3-terminal electronic device

In existing superconducting electronic systems, Josephson junctions play a central role in processing and transmitting small-amplitude electrical signals. However, Josephson-junction-based devices have a number of limitations including: (1) sensitivity to magnetic fields, (2) limited gain, (3) inability to drive large impedances, and (4) difficulty in controlling the junction critical current (which depends sensitively on sub-Angstrom-scale thickness variation of the tunneling barrier). Here we present a nanowire-based superconducting electronic device, which we call the nanocryotron (nTron), that does not rely on Josephson junctions and can be patterned from a single thin film of superconducting material with conventional electron-beam lithography. The nTron is a 3-terminal, T-shaped planar device with a gain of ~20 that is capable of driving impedances of more than 100 k{\Omega}, and operates in typical ambient magnetic fields at temperatures of 4.2K. The device uses a localized, Joule-heated hotspot formed in the gate to modulate current flow in a perpendicular superconducting channel. We have characterized the nTron, matched it to a theoretical framework, and applied it both as a digital logic element in a half-adder circuit, and as a digital amplifier for superconducting nanowire single-photon detectors pulses. The nTron has immediate applications in classical and quantum communications, photon sensing and astronomy, and its performance characteristics make it compatible with existing superconducting technologies. Furthermore, because the hotspot effect occurs in all known superconductors, we expect the design to be extensible to other materials, providing a path to digital logic, switching, and amplification in high-temperature superconductors

Covid‐19 and co‐morbidities: a role for Dipeptidyl Peptidase 4 ( DPP4 ) in disease severity?

The coronavirus disease 2019 (COVID‐19) pandemic is caused by a novel betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), similar to SARS‐CoV and Middle East respiratory syndrome (MERS‐CoV), which cause acute respiratory distress syndrome and case fatalities. COVID‐19 disease severity is worse in older obese patients with comorbidities such as diabetes, hypertension, cardiovascular disease, and chronic lung disease. Cell binding and entry of betacoronaviruses is via their surface spike glycoprotein; SARS‐CoV binds to the metalloprotease angiotensin‐converting enzyme 2 (ACE2), MERS‐CoV utilizes dipeptidyl peptidase 4 (DPP4), and recent modeling of the structure of SARS‐CoV‐2 spike glycoprotein predicts that it can interact with human DPP4 in addition to ACE2. DPP4 is a ubiquitous membrane‐bound aminopeptidase that circulates in plasma; it is multifunctional with roles in nutrition, metabolism, and immune and endocrine systems. DPP4 activity differentially regulates glucose homeostasis and inflammation via its enzymatic activity and nonenzymatic immunomodulatory effects. The importance of DPP4 for the medical community has been highlighted by the approval of DPP4 inhibitors, or gliptins, for the treatment of type 2 diabetes mellitus. This review discusses the dysregulation of DPP4 in COVID‐19 comorbid conditions; DPP4 activity is higher in older individuals and increased plasma DPP4 is a predictor of the onset of metabolic syndrome. DPP4 upregulation may be a determinant of COVID‐19 disease severity, which creates interest regarding the use of gliptins in management of COVID‐19. Also, knowledge of the chemistry and biology of DPP4 could be utilized to develop novel therapies to block viral entry of some betacoronaviruses, potentially including SARS‐CoV‐2

Quality of Life Changes Following Peripheral Blood Stem Cell Transplantation and Participation in a Mixed-Type, Moderate-intensity, Exercise Program

Summary:The purpose of this investigation was to evaluate the impact of undertaking peripheral blood stem cell transplantation (PBST) on quality of life (QoL), and to determine the effect of participating in a mixed-type, moderate-intensity exercise program on QoL. It was also an objective to determine the relationship between peak aerobic capacity and QoL in PBST patients. QoL was assessed via the CARES questionnaire and peak aerobic capacity by a maximal graded treadmill test, pretransplant (PI), post transplant (PII) and following a 12-week intervention period (PIII). At PII, 12 patients were divided equally into a control or exercise intervention group. Undergoing a PBST was associated with a statistically but not clinically significant decline in QoL (P<0.05). Following the intervention, exercising patients demonstrated an improved QoL when compared with pretransplant ratings (P<0.01) and nonexercising transplant patients (P<0.05). Moreover, peak aerobic capacity and QoL were correlated (P<0.05). The findings demonstrated that exercise participation following oncology treatment is associated with a reduction in the number and severity of endorsed problems, which in turn leads to improvements in global, physical and psychosocial QoL. Furthermore, a relationship between fitness and QoL exists, with those experiencing higher levels of fitness also demonstrating higher QoL.Bone Marrow Transplantation (2004) 33, 553-558. doi:10.1038/sj.bmt.1704378 Published online 12 January 200

The intrahepatic signalling niche of hedgehog is defined by primary cilia positive cells during chronic liver injury

Background & Aims: In vertebrates, canonical Hedgehog (Hh) pathway activation requires Smoothened (SMO) translocation to the primary cilium (Pc), followed by a GLI-mediated transcriptional response. In addition, a similar gene regulation occurs in response to growth factors/cytokines, although independently of SMO signalling. The Hh pathway plays a critical role in liver fibrosis/regeneration; however, the mechanism of activation in chronic liver injury is poorly understood. This study aimed to characterise Hh pathway activation upon thioacetamide (TAA)- induced chronic liver injury in vivo by defining Hh-responsive cells, namely cells harbouring Pc and Pc-localised SMO. Methods: C57BL/6 mice (wild-type or Ptc1+/_) were TAA-treated. Liver injury and Hh ligand/pathway mRNA and protein expression were assessed in vivo. SMO/GLI manipulation and SMO dependent/ independent activation of GLI-mediated transcriptional response in Pc-positive (Pc+) cells were studied in vitro. Results: In vivo, Hh activation was progressively induced following TAA. At the epithelial-mesenchymal interface, injured hepatocytes produced Hh ligands. Progenitors, myofibroblasts, leukocytes and hepatocytes were GLI2+. Pc+ cells increased following TAA, but only EpCAM+/GLI2+ progenitors were Pc+/SMO+. In vitro, SMO knockdown/hGli3-R overexpression reduced proliferation/viability in Pc+ progenitors, whilst increased proliferation occurred with hGli1 overexpression. HGF induced GLI transcriptional activity independently of Pc/SMO. Ptc1+/_ mice exhibited increased progenitor, myofibroblast and fibrosis responses. Conclusions: In chronic liver injury, Pc+ progenitors receive Hh ligand signals and process it through Pc/SMO-dependent activation of GLI-mediated transcriptional response. Pc/SMO-independent GLI activation likely occurs in Pc_/GLI2+ cells. Increased fibrosis in Hh gain-of-function mice likely occurs by primary progenitor expansion/proliferation and secondary fibrotic myofibroblast expansion, in close contact with progenitors

Cell migration leads to spatially distinct but clonally related airway cancer precursors

Background Squamous cell carcinoma of the lung is a common cancer with 95% mortality at 5 years. These cancers arise from preinvasive lesions, which have a natural history of development progressing through increasing severity of dysplasia to carcinoma in situ (CIS), and in some cases, ending in transformation to invasive carcinoma. Synchronous preinvasive lesions identified at autopsy have been previously shown to be clonally related. Methods Using autofluorescence bronchoscopy that allows visual observation of preinvasive lesions within the upper airways, together with molecular profiling of biopsies using gene sequencing and loss-of-heterozygosity analysis from both preinvasive lesions and from intervening normal tissue, we have monitored individual lesions longitudinally and documented their visual, histological and molecular relationship. Results We demonstrate that rather than forming a contiguous field of abnormal tissue, clonal CIS lesions can develop at multiple anatomically discrete sites over time. Further, we demonstrate that patients with CIS in the trachea have invariably had previous lesions that have migrated proximally, and in one case, into the other lung over a period of 12 years. Conclusions Molecular information from these unique biopsies provides for the first time evidence that field cancerisation of the upper airways can occur through cell migration rather than via local contiguous cellular expansion as previously thought. Our findings urge a clinical strategy of ablating high-grade premalignant airway lesions with subsequent attentive surveillance for recurrence in the bronchial tree

Liver Graft Revascularization by Donor Portal Vein Arterialization Following “No Touch” Donor Hepatectomy

Unsatisfactory immediate function of the transplanted liver together with technical complications contribute to a persisting early mortality for hepatic transplantation in the 20% range. We report our initial clinical experience with methods, one not previously used clinically, that resulted in uniformly well-functioning liver grafts in 11 patients and contributed to a satisfactory success rate for the procedure. Donors were heart-beating. During the donor operation all manipulations of the liver were avoided until after cold preservation, achieved by external cooling at the same time as circulatory interruption, donor exsanguination and perfusion of the liver with cold oxygenated fluid of “extracellular̵ type. The organs were then gently dissected. At transplantation the livers were revascularized with arterial blood shunted from the recipient iliac artery to the graft portal vein after completion of the suprahepatic IVC anastomosis. The infrahepatic IVCs and hepatic arteries were then joined, the iliac artery shunts discontinued and the portal veins joined. Total ischaemic intervals for the allografts were 3½–8 (average 5). Anhepatic intervals were 1–2¼ (average 2). The arterio-portal shunts were operating for 18–85 (mean 46) min. Blood loss and haemodynamic, acid-base and electrolyte abnormalities at revascularization were minimal. All grafts secreted bile immediately and all parameters reflected continuing improvement of liver function thereafter. Nine patients (82%) are alive between 4 and 18 (mean 11) months after transplantation. We conclude that these methods offer effective avoidance of serious organ damage during donor hepatectomy and preservation, reduced allograft ischaemic interval and reduced recipient anhepatic time. They result in avoidance of blood loss at the time of revascularization, together with minimal haemodynamic, acid-base or biochemical changes. In addition, they allow the surgeon to perform and test all anastomoses without time constraints, provide the capability to deal with unexpected complications, and assure good early graft function

Lessons from the evaluation of the UK's NHS R&D Implementation Methods Programme

Background: Concern about the effective use of research was a major factor behind the creation of the NHS R&D Programme in 1991. In 1994, an advisory group was established to identify research priorities in research implementation. The Implementation Methods Programme (IMP) flowed from this, and its commissioning group funded 36 projects. In 2000 responsibility for the programme passed to the National Co-ordinating Centre for NHS Service Delivery and Organisation R&D, which asked the Health Economics Research Group (HERG), Brunel University, to conduct an evaluation in 2002. By then most projects had been completed. This evaluation was intended to cover: the quality of outputs, lessons to be learnt about the communication strategy and the commissioning process, and the benefits from the projects. Methods: We adopted a wide range of quantitative and qualitative methods. They included: documentary analysis, interviews with key actors, questionnaires to the funded lead researchers, questionnaires to potential users, and desk analysis. Results: Quantitative assessment of outputs and dissemination revealed that the IMP funded useful research projects, some of which had considerable impact against the various categories in the HERG payback model, such as publications, further research, research training, impact on health policy, and clinical practice. Qualitative findings from interviews with advisory and commissioning group members indicated that when the IMP was established, implementation research was a relatively unexplored field. This was reflected in the understanding brought to their roles by members of the advisory and commissioning groups, in the way priorities for research were chosen and developed, and in how the research projects were commissioned. The ideological and methodological debates associated with these decisions have continued among those working in this field. The need for an effective communication strategy for the programme as a whole was particularly important. However, such a strategy was never developed, making it difficult to establish the general influence of the IMP as a programme. Conclusion: Our findings about the impact of the work funded, and the difficulties faced by those developing the IMP, have implications for the development of strategic programmes of research in general, as well as for the development of more effective research in this field